Germicidal soaps composition



Unite GERMICIDAL soAPs COMPOSITION John M. Wenneis, Port Washington, Thomas F. Cleary, North Bellrnore, and Saul Chodrofl, Brooklyn, N. Y., assignors to Norda Essential Oil & Chemical Company, New York, N. Y., a corporation of New York No Drawing. Application March 12, 1953, Serial No. 342,014

8 Claims. (Cl. 252-107) properties, particularly for the destruction of bacteria un-. der normal-conditions of use. If it is to destroy bacteria in contact with the human skin, it must have germicidal activity under these conditions. The germicide must be effective for this purpose in a relatively low concentration in order that it may be economically employed and also utilized in concentrations below that which-would impart 30 any adverse effect. Such a germicide should also be non-toxic, since if it is employed in contact with the human skin it may be ab-- sorbed into the body and would be objectionable if it possessed toxic properties. The undesirability of toxic germicides, such as corrosive sublimate, is too well-known to require elaboration.

Furthermore, an acceptable germicide must be relatively non-irritating to the skin. There are many germicides which destroy bacteria and which are not objectionably toxic but which are irritating when used in contact with the skin in that they cause erythema and in extreme cases produce blisters and pustules.

In addition to being non-irritating, an acceptable germi-- cide must be relatively non-sensitizing. A germicide may be unobjectionable, in that it is non-irritative, upon its first use, but upon repeated use the subject may become sensitive to the germicide so that it cannot be reused without adverse results.

The efiect of chemical structure on any and all of the above properties is not very well understood, if at all, particularly the effect of structure on irritative properties. Changes in chemical structure which amount to no more than a difference of one chlorine atom on aring, or in the position of a chlorine atom, markedly aflfect the results. Compounds so closely related as adjacent homologues similarly give marked dififerences in results. There is, therefore, no predictability from a consideration of chemical structure of the results obtainedin the field of germicidal activity, toxicity, irritative effects, and sensitization.

A large number of compounds have been proposed for inclusion with soap to render it germicidal. Since soap is so universally used in cleansing the'skin, the inclusion of a satisfactory germicide in soap would be an ideal way of destroying bacteria in contact with the human skin. Many compounds which are recognized as germicides have been proposed for combination with soap, especially various phenolic materials, but because 'of the depressing action of soap upon the germicidal properties of known germicidal agents, soaps containing such agents do not have germicidal properties. This effect hasbeen demonstrated and is reviewed at some length in U. S. Patent States Patent C,

2,814,597 I Patented Nov- 26,

No. 2,535,077, dated December 26, 1950. In view of this fact, which is now well-recognized in the art, it is not possible to predict, from the germicidal properties of a chemical compound itself, whether a soap containing it would have satisfactory germicidal activity, and would also meet the other requirements discussed above.

Because of the desirability of a germicidal soap, a great deal of research has been done, and at least one germicidal soap has been placed on the market in which the active ingredient is 2,2 dihydroxy 3,5,6-3,5',6' hexachlorodiphenyl methane (also referred to as Hexachlorophene and 6-11). Although a soap containing this compound is wanting in some respects, as will be pointed out, it has had wide sales and acceptance as an unusual product in which the germicidal activity is retained in the presence of the soap. In view of the fact thatalm'ost twenty-five years of extensive research on a wide variety of compounds preceded the discovery of this particular germicidal soap, it is obvious that the element of predictability is substantially nil and that the discovery of any other compound which could be incorporated in soap with equal or better results would be quite unobvious and unpredictable.

We have discovered, in accordance with our invention, that the following described compounds have germicidal properties and that these properties are retained in soap and that they meet the other desiderata enumerated above,

more particularly non-toxicity, non-irritation, and nonsensitization. These compounds have the following general formula:

gen, especially chlorine, bromine and iodine, and preferably chlorine, and (2) an alkyl or cycloalkyl radical having 1 to 8 carbon atoms; and in which Y and Y are the same or difierent but are the other members selected from the said group. More particularly, if X and'X' are halogen, then Y and Y are alkyl or cycloalkyl, and if X and X are alkyl' or cycloalkyl, then Y and Y are halogen. The alkyl or cycloalkyl radical, for instance, may be methyl, isopropyl, octyl, hexyl, cyclohexyl, etc

The preferred compounds have the general formula:

in which R and R' are the same or dilferent alkyl or cycloallcyl radicals of 1 to 8 carbon atoms, and H1 and H1 are the same or different halogens as defined above,

the preferred compound of this type having the following formula:

CH3 S n =3 The alternative compounds would have the following formula:

H 0 H H1O s -Onr R R where R and R and H1 and HI are as defined above.

Other compounds falling within the invention include,

for example:

OH OH 00Hn0- S "OCaHu Br Br 0H 0H CzHsOS-OCH: C1 CI p A specific embodiment of our invention which we regard at the present time as the best mode that we contemplate for carrying out our invention utilizes the 2- hydroxy-3-methyl-5-ch1oro phenyl sulfide. This compound has a melting point of about 148-l50 C., and is soluble in alcohol, benzene and warm carbon tetrachloride; it is insoluble .in carbon disulfide, hexane and water. pH of soap. This compound is selected as illustrative because of simplicity and economic considerations. Compounds in which the hydrocarbonradical has a larger number of carbon atoms may be preferred from a bactericidal and solubility standpoint.

The compounds of the invention may be made by condensing the appropriate halogenated alkyl or cycloalkyl phenol with sulfur dichloride. An inert solvent or reaction medium may be employed which may or may not be a solvent for the final product. The temperature is not particularly critical. as long as the reaction takes place at a rate which is controllable. Inasmuch as the reaction proceeds satisfactorily at room temperature, this is preferably employed, since it obviates the need for refrigeration or maintenance, of elevated temperatures. A catalyst is not required, nor is extended refluxing essen tial. The final product is separated from the reaction medium by filtration and can be washed, and if necessary recrystallized to obtain a purer product.

As illustrative of the best mode of practicing the process of preparing the preferred compound of the invention, 28.4 grams of p-chloro-o-cresol and 251 cc. of solvent is placed in a flask and to it is added drop-wise, over a period of about fifteenminutes, 10.2 grams of sulfur dichloride in cc. of the solvent. The mixture is stirred It is, however, soluble in soap at the normal during the addition, which is carried out at room temperature (20-30" C.). The stirring of the mixture is continued until the evolution of hydrogen chloride ceases, which generally requires from thirty minutes to three hours. During this time, the product crystallizes if a solvent is employed in which the reaction product is insoluble. The product is filtered and washed colorless with the solvent generally in an amount of 50-100 cc. The combined filtrates may be stripped of solvent and unreacted sulfur dichloride, preferably in vacuo, to yield oily solids. However, it is difiicult to salvage a clean product from such a residue.

The solvent employed in the reaction can influence the yield, ease of handling, and cleanliness of the product.

When carbon disulfide is employed as the solvent, a reaction medium commonly used for this type of reaction, the initial yield is 82%, the product having a melting point of 126 C. Upon recrystallization the yield is reduced to 56%, the product having a melting point of 148 C. The high crude yield is not indicative of the final results, since the material salvaged from the second crop of crystals cannot be successfully handled to give a clean product under usual circumstances. For practical purposes, therefore, the yield from carbon disulfide may be considered 56% When ethylene dichloride is used, the crude yield is 60%, the product melting at 149 C. When hexane is used as the solvent, the crude yield is 66%, the product melting at 130 C. These crude yields were washed in hexane and not recrystallized. Further losses would be obtained upon recrystallization.

In another variation of the process, the reaction medium may be an ester in which the alcohol and acid radicals have 5 carbon atoms or less, for instance isopropyl acetate. In such solvents, all of the reaction components are soluble, as well as the resulting product, including a large portion of the hydrogen chloride. At the conclusion of the reaction, the product is neutralized with sodium carbonate and stripped of hydrogen chloride.

The solvent is evaporated and the resulting product may be recrystallized from any suitable solvent, such as hexane.

The preferred solvent consists of a mixture of ethylene dichloride and hexane, such as, for example, 10 to 50% by volume of ethylene dichloride and to 50% hexane, preferably 22% ethylene dichloride and 72% hexane. The yield from this solvent is 63%, the product having a melting point of 148 C. This initial product is clean and does not need recrystallization. This solvent is preferred because of the higher yield as compared with the yield of recrystallized product when carbon disulfide is used as the solvent and also because of the elimination of recrystallization.

In a modification of this process in which the hydrogen chloride is swept out by bubbling with air until no more hydrogen chloride is evolved, followed by treating the reaction mixture with a slightexcess of sodium carbonate solution, the product obtained by filtration and washing with hexane amounted to a yield of 72% without recrystallization.

The use of excess sulfur dichloride does not increase the yield, nor does the use of a chlorine carrier catalyst, such as aluminum chloride, result in advantages; such a catalyst, in fact, reduces the yield and gives a darker product. Refluxing does not afiect the yield and leads to a darker product.

The product made by any of the above processes can be decolorized, if desired, by dissolving it in methanol, adding a small amount of activated carbon, such as Darco G-60, at elevated temperature below the boiling point of the methanol, and filtering. The product is precipitated by adding water to the hot solution and cooling gradually with stirring.

In order to demonstrate the effectiveness of the compounds of the present invention as germicides, particularly in. soap, a germicidal soap composition was prepared as the base a pure white soap of the type con 'ventionallyemployed for toilet purposes (Ivory), in which was thoroughly incorporated 2% of 2-hydroxy-3-methyl- S-chloro phenyl sulfide. This was tested in comparison with a similar soap containing 2% of Hexachlorophene. These two soaps were tested to determine the skin-degerming efiiciency on six subjects each, according to the method of Arthur R. Cade, An in vivo method for determining the de-germing efiiciency of soaps containing Hexachlorophene, Papers on Evaluation of Soaps and Detergents, Special Technical Publication No. 115, published by the American Society for Testing Materials, 1952.

While this test is fully described in the above publication, it may be summarized as follows: 'Iwelve subjects were used for the test. They were divided into two groups of six subjects each, three males and three females in each group, which were used to test each of the above two soaps. Each subject was given two cakes of soap corresponding to his or her group, one for use at home and the other at work. No subject had used any germicidal soap for at least two weeks prior to the test. The test was started me Monday and ended on the second Friday following, during which time the subjects used their allotted soap when washing their hands. The transient and resident bacterial population on the hands of each subject was determined on the first day prior to starting the use of the experimental soap. The transient and resident bacterial population on the hands of each subject was also determined on the Friday of the first week, after four days use of the soap, and on the Thursday and Friday of the second week, after nine and ten days use of the soap.

The details of the method are given in the publication referred to above. Briefly, the method consists in having each subject wash his hands with a. bland, non-germicidal, neutral soap, five consecutive times, the first, fourth and fifth times, in separate basins containing 2 liters of lukewarm water. The second and third times the hands were washed under running lukewarm tap water. Bacterial counts were taken on the wash waters in the basins, which represent the first, fourth and fifth washings. The counts on the first washing are considered to be predominantly the transient bacterial population of the skin, whereas the counts on the fourth and fifth washings are considered to be predominantly the resident bacterial population of the skin.

Since the effectiveness of a germicidal soap will be demonstrated primarily by the reduction in the resident bacterial population rather than the transient, the results are expressed as the reduction obtained on the fifth washing. The mean figure is obtained by discarding the two highest and the two lowest values and averaging the remaining two. The mean does not take into consideration a subject who may be out of line with the other subjects. The results are given in the following table:

Reduction in the resident bacterial population (5th washing) It will be obvious that considering both the mean and the average, the soap made in accordance with the invention is as good, and in some instances better than the soap containing Hexachlorophene, which may be considered as the standard reference. As has been explained heretofore, the discovery of Hexachlorophene as a germicide for soap was the result of years of research and is widely accepted as an unusual development in the germicidal soap field. The development of any other soap which equalled this at this stage of the art would be quite unexpected.

The toxicity of the preferred compound of the invention, namely, 2-hydroxy-3-methyl-5-chloro phenyl sulfide, was determined by administering the compound orally to rats. p The method employed is the LD50 test which may be defined as the amount which, when administered orally as a single dose, will probably kill 50% of the animals to which it is administered. In carrying out the test, normal healthy white albino rats, paired for sex, fasted for 24 hours,'were administered various dosages of the compound (dissolved in corn oil) by stomach tube. All animals were observed for at least two weeks following the administration of the dosage, unless death occurred before that time. The results are given in the following table:

When the results were plotted on semilogarithmic paper, with the percent mortality on the ordinate and the dose on the abscissa (logarithmic scale), the LDso of the compound was found to be approximately 1.3 grams of the compound per kilogram body weight.

As will be obvious to one skilled in the art, this low toxicity, when measured by this standard test, is assurance that the compound is sufficiently safe for use as a germicide in soap.

In order to determine the irritative properties of 2- hydroxy-3-methyl-5-chloro phenyl sulfide, and particularly to compare it with the irritative properties of Hexachlorophene, these two compounds were tested, as well as the sodium salt of both compounds, since the sodium salt probably corresponds to the form of the compound present in soap. The solutions tested were as follows:

Solution A: 0.5% 2-hydroxy-3-methyl-5-chloro phenyl sulfide in aqueous isopropyl alcohol Solution B: 0.5 Hexachlorophene in aqueous isopropyl alcohol Solution C: 0.5 sodium salt of 2-hydroxy-3-methyl-5- chloro phenyl sulfide in aqueous isopropyl alcohol Solution D: 0.5% sodium salt of Hexachlorophene in aqueous isopropyl alcohol Each solution was tested by the well-known patch test to determine if the compounds would produce contact dermatitis on primary contact. In this test 55 human subjects, 34 females and 21 males, ranging from ten to sixty-three years, were employed. Discs approximately 1 cm. in diameter were cut from white blotting paper and different discs saturated with the four solutions described above. The saturated discs were applied to the flexor surface of either the forearm or the upper arm of each subject, utilizing four patches for each subject. All patches were covered with an Elastopatch. After twenty-four hours of primary contact with the patches, they were removed and the subjects examined. The reactions obtained on every subject following examination were noted, and the severity of reaction was based ,on an arbitrary scoring system, as follows:

2=Rather severe erythema or discoloration lasting at.

least two days after removal of the patch.-

3=Severe circumscribed irritation with blisters or pustules.

The results are given in the following table, which lists the number of subjects in each reaction category:

From a consideration of the above results, it will be obvious that the compound of the invention, as well as the sodium salt thereof, are much less irritating than the Heixachlorophene. This is particularly true in the case of the sodium salt, the form in which the compound would exist in soap, where the Hexachlorophene is found to be almost again as irritating as the compound of the invention.

In order to determine the sensitizing properties, the irritation test was repeated on each of the subjects by applying patches with the same solution to the same subject, each patch being applied at the site previously used for that particular patch. The patches were again worn for twenty-four hours and the subjects examined in the same manner as described above. The results are given in the following table:

From this it will be seen that as compared with Hexachlorophene the compounds of the invention cause less sensitization, and that this is particularly true in the case of the sodium salt of the compound, where the Hexachlorophene is shown to be almost twice as objectionable as the preferred compound of the invention from the standpoint of sensitization.

A low sensitization level is an extremely important aspect of compounds used in germicidal soaps because of the repeated use of such soaps under normal living conditions. It will be obvious that a soap is useless for nor mal toilet use if it cannot be utilized over long periods of time. To substantiate the non-sensitizing properties of the preferred compound of the invention, the sensitization was determined on white .male guinea-pigs by the method described in an article entitled Methods for the study. of irritation and toxicity of substances applied topically to the skin and mucous membranes," John H. Draize, Geoffrey Woodard and Herbert O. Calvery, Journal ofPharmacology and Experimental Therapeutics, vol. 82, No. 4, pages 386-388, December 1944. In this method, ten white male guinea-pigs, weighing 325-450 grams, were used. The hair was removed from the back by close clipping. A 0.1% suspension of the compound in water was injected intracutaneously, using a 26-gauge needle. A total of ten injections were made at random in an area about three to four centimeters square, just below the midline of the back. The first injection was 0.05 ml., while the remaining injections were 0.1 ml. Two weeks after the tenth injection, .a test injection of 0.05 ml. of a freshly-prepared suspension was made on the flank, slightlybelow the sensitizing area. Twenty-four hours later, a reading of the diameter, height and color of the reaction was made and compared with similar readingstaken after the first injection.

As a result of this test, it was found that on all ten animals the values for the test readings were no greater than those for the initial readings, and it is concluded that when tested by the above procedure the preferred compound of the invention cannot be considered to be a sensitizer.

The compounds of the invention may be used in soaps, in the so-called non-soap synthetic organic detergents, or in combination with any organic detergent. This expression is intended to include the soaps which are the salts of higher fatty :acids and the so-called non-soap synthetic detergents. All of these compounds .are characterized by an organic radical having at least 8 carbon atoms and a group or grouping imparting sufiicient hydrophilic, water-.solubilizing or water-dispersible properties to give the detergent satisfactory washing properties in water. These organic detergents are to be distinguished from the inorganic detergents, such as the silicates, phosphates, etc., which possess detergent properties but which donot ordinarilyhaye the property of inhibiting the germicidal activity of germicides as do the soaps and synthetic non-soap detergents.

The soap maybe any of those commercially utilized in the household or in industry. These are generally the sodiumsoaps of fatty acids having 12 to 18 carbon atoms, such as lauric, myristic, .palmitic, oleic, stearic, etc., or mixtures thereof. The mixtures of fatty .acids derived from tallow and coconut oil are illustrative. A portion of the sodium soap may be replaced by potassium soap. As a specific illustrative example, the soap may consist of 75% tallowfatty .acids and 25% coconut oil fatty acids saponified with sodium hydroxide. In another specific example, 10% of the sodium hydroxide is replaced by potassium hydroxide. ,The soap may contain antioxidants, pigments, dyes, perfume, etc, as is conventional.

The non-soap organic detergents may be of the so-called anionic, nonionic or cationic type. Illustrative detergents of this type are described in Industrial and Engineering Chemistry, vol. 35, page 107 et seq. and page 126 ct seq. (1943). As specific examples may be mentioned sodium lauryl sulfate (Duponol) and sodium polypropylene benzene sulfonate in which the polypropylene radical contains 10 to 15 carbon atoms (Oronite). Others include the sulfonated monoglycerides of fatty acids, the sodium fatty acid taurides, and methyl taurides such as sodium oleic methyl tauride .(Igepon T), coconut fatty alkyl dimethylbenzylammonium chloride (Triton K-), coconut fatty acid diethanolamide (Ninol), and similar detergents.

The amount of the compound to be incorporated in the detergent will be controlled somewhat by economic considerations and the extent of the germicidal activity desired in the detergent. Amounts as low as a fraction of 1%, for example 0.25 to 0.5%, show a significant improvement in germicidal action. Larger amounts, however, of the order of 1.5 to 3.0% are preferred, 2.0% appearing to be an optimum. Amounts larger than 3% to 5% are .uneconomical, and the use properties are not sufficiently important under the usual circumstances to justify such larger amounts.

The compounds of the invention may be included in soap or detergents in any form, such as in cakes or bars of the type generally sold and used for the toilet, in the all-purpose type, such as the white floating bar, or in powders, liquids, flakes, beads, and similar forms.

The compounds may be incorporated in the soap in any manner. If the soap is a liquid, the compound may simply be dissolved therein; if it is a solid, the compound may be incorporated at any stage of the manufacture, such as in the kettle, the mill, the plodder, the crutcher, etc. so long as uniform distribution is obtained.

9 We claim: 1. The compound having the following formula:

OH OH ornO-s-Oom e1 01 2. A method of preparing the compound of claim 1 which comprises reacting sulfur dichloride with p-chloroo-cresol in approximately stoichiometric proportions at a temperature Within the range of 20 to 30 C., the sulfur dichloride being added gradually to the p-chloro-o-cresol, both the sulfur dichloride and the p-chloro-o-cresol being dissolved in a reaction medium consisting essentially of from 10 to 50% by volume of ethylene dichloride and from 90 to 50% by volume of hexane, the reaction being carried out with stirring during the addition of the sulfur dichloride until the evaporation of hydrogen chloride ceases.

3. The method of claim 2 in which the reaction is followed by bubbling air through the reaction mixture to strip hydrogen chloride therefrom.

4. The method of claim 2 in which the reaction me- 10 dium comprises about 22% ethylene dichloride and about 72% hexane.

5. The method of claim 2 in which the reaction medium is about 22% ethylene dichloride and about 72% hexane, and in which the reaction is followed by bubbling air through the reaction mixture to strip hydrogen chloride therefrom.

6. A germicidal detergent composition comprising a fatty acid soap and an amount of the compound of claim 1 to render the composition germicidal.

7. The composition of claim 6 in which the fatty acid soap is a toilet soap in bar form.

8. The composition of claim 7 in which the amount of the compound incorporated is about 2%.

References Cited in the file of this patent UNITED STATES PATENTS Cook et al. Ian. 13, 1942 Kunz et al. July 18, 1944 OTHER REFERENCES Jour. Chem. Soc., London (1937), 

1. THE COMPOUND HAVING THE FOLLOWING FORMULA:
 6. A GERMICIDAL DETERGENT COMPOSITION COMPRISING A FATTY ACID SOAP AND AN AMOUNT OF THE COMPOUND OF CLAIM 1 TO RENDER THE COMPOSITION GERMICIDAL. 